WO2006087996A1 - Process for production of carbapenem derivative and crystalline intermediate therefor - Google Patents

Abstract

Disclosed is an intermediate for the synthesis of a carbapenem which is advantageous for the industrial production of the carbapenem. A process for producing a compound (I) or a pharmaceutically acceptable salt or solvate thereof or a crystal thereof, comprising reacting a compound (III) with a compound (IV) in the presence of a secondary amine; a crystal of a benzyl alcohol-solvated form of the compound (I) or the like; a method for deprotecting the compound (I) by using a Pd catalyst; and a crystal of the compound (IV) or the like.

Description

 Preparation of strong rubapenem derivative and its intermediate crystals

 Technical field

 [0001] The present invention relates to a method for producing a powerful rubapenem derivative and an intermediate crystal thereof.

 Background art

 [0002] A pyrrolidylthio-powered rubapenem derivative (compound (II)) having a broad antibacterial spectrum is known as a useful antibiotic (Reference: Patent Document 1). The compound (I) of the present invention is a synthetic intermediate.

 [Chemical 1]

(Wherein R ¹ is a carboxy protecting group: R ² is an amino protecting group)

 As an example of the production method of compound (I), the following method is described in Patent Document 1 (Example 13, Step 3), but the base used in the condensation reaction for introducing the 2-position side chain is: ,

 Ethylamine (71% yield).

 [Chemical 2]

 (l l l-a) (IV-a) (I -a)

Also, Patent Document 2 (Reference Example 1) describes the same reaction shown below, but the base used in the condensation reaction is also diisopropylethylamine (yield 54%).

Furthermore, the synthesis method of force rubapenem derivatives having a pyrrolidinylthio group of another structure at the 2-position is well known. Diisopropylethylamine is also used as the base for the condensation reaction at the force 2-position (see: Patent document 3, Example 7 etc.)

 As described above, tertiary amines such as diisopropylpropylamine are generally used as bases for the second-position condensation reaction of force rubapenem. This is probably because tertiary amines are generally strongly basic and there is no hydrogen on the N atom, so side reactions are unlikely to occur! /.

 Regarding the crystallization of the above compound (Ia), various alcohol solvate crystals (Examples: 2-propanol, 2-pentanol, 1 pentanol, tamyl alcohol, 1 propanol) are known. (Reference: Patent Document 2).

 The compound (IV-a), which is a synthetic intermediate of the compound (I a), is described in Patent Document 1 (see: Production Example 8), but the crystal is isolated! / ! /

 Furthermore, as a deprotection method for compound (Ia), Sn reagent (Reference: Patent Document 1) and Meldrum's acid (Reference: Patent Document 2) were used! From the standpoint of sexuality, it was favorable for industrial implementation. On the other hand, a combination of an amine and a Pd catalyst is known as a deprotection reagent for other powerful rubapenem derivatives (see Patent Document 4). In Patent Document 4, amines are used as acceptors for lower alkyl groups. Examples of preferred amines include aromatic amines such as arrin and N-methylarin. Patent Document 1: Japanese Patent Laid-Open No. 05-294970

Patent Document 2: WO2004Z72073 Publication

Patent Document 3: Japanese Patent Laid-Open No. 02-15080

Patent Document 4: Japanese Patent Application Laid-Open No. 64-79180

Disclosure of the invention Problems to be solved by the invention

 [0003] Development of a more preferable industrial process for the compound (I), which is an intermediate of a powerful rubapenem derivative, has been demanded. There is also a demand for the development of a more preferable crystal of the compound (I). Further, there is a demand for industrially preferable deprotection methods for compound (I) and development of crystals such as compound (IV-a) which is an intermediate of compound (I).

 Means for solving the problem

[0004] As a result of intensive studies in view of the above problems, the present inventor has improved the reaction yield by using a specific base, preferably a secondary amine, during the second-position condensation reaction of force rubapenem. It was found that the reaction time was shortened and compound (I) could be produced efficiently. It was also found that if compound (I) is crystallized with benzyl alcohol isotropic, crystals having excellent handling as an intermediate can be obtained. Furthermore, a method for deprotecting compound (I) in the presence of a Pd catalyst and a specific amine, and crystals such as compound (IV-a) were found, and the present invention shown below was completed.

(1 set:

 [Chemical 4]

Wherein R is hydrogen or a hydroxy protecting group; R ¹ is a carboxy protecting group; Ph is

 Compound (III) represented by the formula:

 [Chemical 5]

(Wherein R ² is an amino protecting group)

Is reacted with the compound (IV) or a pharmaceutically acceptable salt thereof in the presence of a secondary amine. And optionally deprotecting the hydroxy protecting group, wherein:

 [Chemical

(Wherein R ¹ and R ² are as defined above)

Or a pharmaceutically acceptable salt, solvate or crystal thereof.

 (2) The production method according to the above (1), wherein the secondary amine is diisopropylamine.

!? (3) ¹ CH CH = CH; is R ² is COOCH CH = CH, a manufacturing method of the above 1 or 2, wherein

 2 2 2 2

(4) A compound (I), a pharmaceutically acceptable salt, a solvate or a crystal thereof is obtained by the method described in any one of 1 to 3 above, and then subjected to a deprotection reaction. And the formula:

 [Chemical 7]

で示される化合物 (11)、その製薬上許容される塩、またはそれらの溶媒和物の製造 方法。

Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

 Equation (5):

で示される化合物 (I a)の溶媒和物結晶（但し、該溶媒は、置換されていてもよいべ ンジルアルコールである）。

A solvate crystal of the compound (Ia) represented by the formula (provided that the solvent is an optionally substituted benzyl alcohol).

 (6) The crystal as described in 5 above, which is a benzyl alcohol solvate crystal.

 (7) Content of benzyl alcohol The crystal according to 3 above, which is 1 to 10 molar equivalents relative to compound (I).

 (8) The crystal according to 6 or 7 above, wherein in the powder X-ray diffraction pattern, main peaks are present in the vicinity of diffraction angles 20 = 7.6, 17.7, 18.5, 19.5, 19.9, 21.3, 23.8 (unit: degree).

(9) Deprotecting the crystal according to any one of 5 to 8 above,

[Chemical 9]

で示される化合物 (11)、その製薬上許容される塩、またはそれらの溶媒和物の製造 方法。

Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

 (10) After obtaining Compound (I), a pharmaceutically acceptable salt thereof or a solvate thereof by the method described in any one of 1 to 3 above, this may be substituted, and benzyl alcohol The compound (I), wherein the compound (I) is substituted by crystallization to obtain a benzyl alcohol solvate crystal, which is deprotected. A method for producing an acceptable salt or a solvate thereof.

 Equation (11):

[Chemical 15]

(Wherein R ¹ is a carboxy protecting group; R ² is an amino protecting group)

A compound represented by the formula: Characterized by deprotection in the presence of aniline, the formula:

 [Chemical 16]

で示される化合物 (11)、その製薬上許容される塩、またはそれらの溶媒和物の製造 方法。

Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(12) The production method according to (11), wherein 1 ^ is CH ² CH═CH; R ² is COOCH CH═CH.

 2 2 2 2

 (13) The amount of Pd catalyst used The production method according to the above (11), which is 0.01 molar equivalent or less with respect to the compound (I).

 (14) The amount of Pd catalyst used The production method according to (11) above, wherein the amount is 0.005 molar equivalent or less relative to compound (I).

 Equation (15):

で示される化合物の結晶。 [Chemical 17]

A crystal of the compound represented by

 (16) In the powder X-ray diffraction pattern, the main peak is around diffraction angle 20 = 6.26, 12.50, 18.24, 18.80, 23.90, and 26.86 (unit: degree). The crystal according to (15), which is present.

 Equation (17):

(式中、 Acはァセチル； Bocは t ブトキシカルボ-ル）

(In the formula, Ac is acetyl; Boc is t-butoxycarbol)

 A crystal of the compound represented by

 (18) In the powder X-ray diffraction pattern, the main peaks are diffraction angles 2 0 = 10. 24, 12. 2 6, 13. 34, 17. 32, 20. 84, 21. 22, 21. 72, and 22 28. The crystal according to (17) above, present in the vicinity of 28 (unit: degree).

 The invention's effect

 [0005] According to this production method, compound (I) can be produced in a short period of time based on yield. Also, a solvate crystal of compound (I) excellent in handling can be obtained. The present invention also provides a method for deprotection of Compound (I) in the presence of a Pd catalyst and an intermediate crystal. By using these production methods and crystals, a compound (Π), a solvate thereof, or a crystal thereof, which is a carbapenem antibacterial agent, can be efficiently produced.

 Brief Description of Drawings

 FIG. 1 is a chart of a powder X-ray diffraction pattern of a benzyl alcohol solvate crystal of compound (I a) obtained in Example 1.

 FIG. 2 shows a peak value of a powder X-ray diffraction pattern of a benzyl alcohol solvate crystal of compound (Ia) obtained in Example 1.

 FIG. 3 is a chart of a powder X-ray diffraction pattern of a crystal of the compound (IV-a) obtained in Example 7.

 FIG. 4 is a chart of a powder X-ray diffraction pattern of a crystal of the compound (Va) obtained in Example 7.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0007] (1) Production method of compound (I)

 [Chemical 10]

(式中、 Rは水素またはヒドロキシ保護基； R¹はカルボキシ保護基； R²はァミノ保護基 、 Phはフエ-ル） 化合物 (ΠΙ)と化合物 (IV)またはその製薬上許容される塩を塩基存在下に反応させ た後、所望によりヒドロキシ保護基を脱保護することにより、化合物 (1)、その製薬上許 容される塩、その溶媒和物またはそれらの結晶が得られる。

(Wherein R is hydrogen or a hydroxy protecting group; R ¹ is a carboxy protecting group; R ² is an amino protecting group, Ph is a phenol) Compound (ΠΙ) and Compound (IV) or a pharmaceutically acceptable salt thereof After the reaction in the presence of a base, the hydroxy protecting group is optionally deprotected to give compound (1), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystal thereof.

As the base, a secondary amine is used, more preferably a secondary amine having a relatively large steric hindrance. Specifically, it is represented by NHR ^a R ^b , and R ^a and R ^b are each independently alkyl or phenol, and preferably R ^a and R ^b are the same. Alkyl is straight-chain or branched C1-C10, preferably C3-C7 alkyl, more preferably branched. More preferable examples of R ^a and R ^b include isopropyl, t-butyl, isobutyl, amyl, and file. As the secondary amine, diisopropylamine, di-t-butylamine, diisobutylamine, diamylamine, and diphenylamine are more preferable, and dialkylamine (eg, diisopropylamine) is particularly preferable.

 Examples of the reaction solvent include acetonitrile, dimethylformamide, methylene chloride, dimethyl sulfoxide, N dimethylacetamide and the like, and N dimethylacetamide is preferable.

 The reaction temperature is generally 40 ° C to room temperature, preferably about 20 to 0 ° C.

 The reaction time is usually several tens of minutes to several tens of hours, preferably 1 to 5 hours.

The amount of compound (III) and compound (IV) used is 10: 1 to 1:10, preferably 1: 1 to L: 5. As the pharmaceutically acceptable salt, an inorganic base salt (eg, sodium) Al metal salts such as salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; organic base salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanol salt) Amine salts, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine salts); inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate; formate, acetate, trifluoro Organic acid addition salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate; basic amino such as arginine, aspartic acid, glutamic acid And salts with acid or acidic amino acids.

 As the hydroxy protecting group represented by R, various hydroxy protecting groups that can be generally used in the field of β-ratata antibacterial agents can be used. Specific examples thereof include trialkylsilyl (the alkyl is preferably C1-C6, eg, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylpropylsilyl, dimethylhexylsilyl, tert-butyldiphenylsilyl), substituted. !, But benzyl (examples of substituents: nitro, lower alkoxy), lower alkoxy carbo groups (eg, methoxy carbo yl, ethoxy carbo ol), halogeno lower alkoxy carbo ol groups, substituted However, benzyloxycarbol (substituent examples: nitro, lower alkoxy), acyl (eg, acetyl, benzoyl), aralkyl (eg, trimethyl), tetrahydrobiral, etc. It is done. Trialkylsilyl, particularly trimethylsilyl and t-butyldimethylsilyl are preferred.

 These hydroxy protecting groups can be deprotected after the reaction, if desired, by methods well known to those skilled in the art. Further, it may be a protecting group that is automatically removed during the coupling reaction or in the post-treatment (eg, extraction, washing) stage. For example, trimethylsilyl and the like are eliminated by acid in the extraction operation after the reaction.

The carboxy protecting group represented by R ¹ includes lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl), lower alkanoyloxy (lower) alkyl (eg, Acetoxymethyl, propio-loxymethyl, butyryloxymethyl, valeryloxymethyl, bivalyloxymethyl, hexanoloxymethyl), lower alkanesulfo-loxy (lower) alkyl (eg 2-mesylethyl), mono (or di or Tri) halo (lower) alkyl (eg, 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarboxoxy (lower) alkyl (eg, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxyme) Chill, tertiary butoxy Ruboxyloxymethyl, 1 (or 2-) methoxycarboxoxyl, 1 (or 2-) ethoxycarboxoxyl, 1 (or 2-) isopropoxycarboxoxyl), lower alkenyl (eg, bur, allyl), Low-grade alkyl (eg Etul, Probule), (Substituted) aryl (Lower) alkyl (eg Benzyl, 4-methoxybenzyl, 4-trobenzyl, phenethyl, trityl, benzhydryl) , Bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-hydroxy 3,5-ditertiary butylbenzyl), (substituted) aryl (eg, phenyl, 4-cylinder, tolyl, Tertiary butylphenol, xylyl) and the like. Among these, as R ¹ , the advantage of using this production method in the case of a protective group of a relatively electrophilic type is great. Preferably, lower alkyl, lower alkyl (eg, bur, aryl), Lower alkyl, (substituted) aryl, (lower) alkyl, or (substituted) aryl. More preferably, it is a protecting group that is difficult to be removed during the coupling reaction, and particularly preferred is aryl (one CH 2 CH═CH 2).

 twenty two

Examples of the amino protecting group represented by R ² include an aliphatic acyl group derived from carboxylic acid, carbonic acid, sulfonic acid and carbamic acid, and an aliphatic acyl group substituted with an aromatic group.

 Aliphatic acyl groups are saturated or unsaturated acyclic or cyclic acyl groups, such as, for example, lower alkanol groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl and the like. Alkanoyl groups such as mesyl, ethylsulfol, propylsulfol, isopropylsulfol, butinolesnorehoninore, isobutinoresnorehoninore, pentinoresnorehoninore, hexinoresnorephonyl, etc. Alkylsulfol groups such as lower alkylsulfol groups, rubamoyl groups such as N-alkyl rubamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl , Tertiary butoxy Alkoxycarbon groups such as lower alkoxy carbo groups such as rubols, for example, alkke groups such as lower alkoxy carboxy groups such as buroxy carboxy and aralkyl carboxylic groups. Alkoxyl groups such as alkoxyl groups such as lower alkenyl groups such as acryloyl, methacryloyl, crotonol, etc. Cyclo (lower) alkanecarbox such as cyclopropanecarbol, cyclopentanecarbol, cyclohexanecarbol etc. And cycloalkane carbo yl group such as -l group.

Examples of the aliphatic acyl group substituted with an aromatic group include aralkoxycarbons such as vinyl (lower) alkoxycarbonyl groups such as benzyloxycarbol and phenoxycarboxyl. Group. These acyl groups may be further substituted with one or more suitable substituents such as -tro group. Preferred acyl groups having such a substituent include, for example, -troayloxycarbol and the like. Examples include a larcocarboxyl group.

 The amino protecting group is preferably a protecting group which is not easily eliminated during the coupling reaction, and particularly preferably an alkoxycarboxyl group (eg, COOCH CH═CH 3).

 twenty two

(2) Compound (I a) crystals

 Compound (Ia) can be crystallized from an alcohol solvent. The alcohol is preferably substituted and is benzyl alcohol, and the alcohol solvate crystals are obtained. As the substituent of the benzyl alcohol which may be substituted, lower alkyl, preferably C1-C4 alkyl (eg, methyl, ethyl, propyl), lower alkoxy (eg, methoxy, ethoxy, propoxy), Halogen (eg: F, Cl, Br), optionally substituted amino (example of substituent: lower alkyl), nitro, silane-containing OH, etc. are exemplified, and the substitution position is either ortho, meta or para. Good.

 As an optionally substituted benzyl alcohol solvate crystal, a benzyl alcohol solvate crystal is preferably obtained. The content of benzyl alcohol in the benzyl alcohol solvate crystal is 0.1 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, more preferably 1 molar equivalent, relative to compound (Ia). . The benzyl alcohol solvate crystal preferably exhibits the pattern of FIG. 1 in powder X-ray diffraction.

 The benzyl alcohol solvate crystal preferably has a main peak at least in the vicinity shown below in the powder X-ray diffraction pattern.

 2 Θ = 7.6, 17.7, 18.5, 19.5, 19.9, 21.3, 23.8 (unit: degree)

(X-ray diffraction measurement conditions: tube CuK o; line, tube voltage 30 Kv, tube current 15 mA, dsin θ = η λ (η is an integer, θ is the diffraction angle))

The interplanar spacing d value is selected from the main peaks having a high relative intensity among the X-ray peaks, and the crystal structure is not necessarily limited only by these values. That is, peaks other than these may be included. In general, when a crystal is measured by X-ray analysis, the peak may cause some measurement error due to the measuring instrument, measurement conditions, presence of attached solvent, and the like. For example, a measurement error of about ± 0.2 occurs as the value of surface separation d In some cases, even if very precise equipment is used, a measurement error of about ± 0.01 to 0.1 may occur. Therefore, some errors should be taken into account in identifying the crystal structure, and all crystals characterized by X-ray patterns substantially similar to those described above are within the scope of the present invention.

 When the benzyl alcohol solvate crystal is prepared from the compound (I a), it is preferable to dissolve the compound (I a) or a solvate thereof in a soluble solvent, It can be obtained by stirring for several hours at room temperature, allowing to stand at 0 ° C to room temperature for several hours to several days, and then filtering and drying by a conventional method. Also. After dissolving the compound (Ia) or its solvate in a large amount of solvent, the solvent is once distilled off to obtain a concentrated solution. To this, benzyl alcohol and other organic solvent as required are added, As described above, stirring, filtration, drying and the like may be performed.

 Examples of the solvent include the following soluble solvents, insoluble solvents and mixed solutions thereof.

 Soluble solvents include methanol, ethanol, ethylene glycol, methoxyethanol, glycerol, propylene glycol and other alcohols, dioxane, tetrahydrofuran, dimethoxyethane, and other ethers, acetone, methyl ethyl ketone, methyl isobutyl ketone, and other ketones. , Esters such as methyl formate, ethyl acetate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, dichloromethane, chloroform, Organic halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, trichloroethane, black benzene and dichlorobenzene, -tolyls such as acetonitrile and propio-tolyl, dimethyl Fuorumuamido, dimethyl sulfoxide, N- methylpyrrolidone, quinoline, pyridine, and the like can be used Toryechiruamin. These solvents may be used alone or in combination of two or more. It can also be used by mixing water. Preferred is ethyl acetate.

Examples of insoluble solvents include alcohols such as 2-propanol, 2-pentanol, 1 pentanol, tamyl alcohol, 1 propanol, n propanol, t-butanol, isobutanol, n-butanol, cyclohexanol, and benzyl alcohol. The Ethers such as ethinoreethenole, isopropinoleetenore, dibutinoleethenole, ethinoreisoaminolethele, ethylphenol ether, n pentane, n-hexane, n-heptane, n octane, n Hydrocarbons such as decane, cyclohexane, methylcyclohexane, toluene, benzene, ethylbenzene, tamen, cymene, and xylene can be used. These solvents may be used alone or in combination of two or more. The use ratio of the soluble solvent and the insoluble solvent is usually 1: 0 to 1: 1000, preferably 1: 0.1 to 1: 100, particularly preferably 1: 1 to 1:50 in weight ratio, or Usually, 0: 1 to 1000: 1, preferably 0.1: 1 to 100: 1, particularly preferably 1: 1 to 50: 1. Preferably, ethyl acetate and benzyl alcohol are used in a ratio of 1: 1 to 5.

 The benzyl alcohol solvate crystal of compound (Ia) has very good crystallinity, as is clear from the clarity of its X-ray peak. Therefore, when compound (Ia) is synthesized by a 2-position condensation reaction and isolated as a benzyl alcohol hydrate crystal, the desired product is obtained with high yield and high purity. Moreover, the handleability is good and the storage stability is high. Therefore, it is very useful as an intermediate for the synthesis of compound (ii), a carbapenem antibacterial agent. When isolating compound (Ia) as a benzyl alcohol solvate crystal from the reaction solution after the 2-position condensation reaction, the reaction extract is preferably washed, evaporated, and dried, as described above. Crystallization may be achieved by dissolving in a soluble solvent and calorifying benzyl alcohol and optionally other insoluble solvents. In addition, when benzyl alcohol is added, benzyl alcohol solvate crystals of the compound (Ia) separately prepared as required may be added as seed crystals.

(3) Step of deprotecting compound (1), its solvate or crystals thereof

 By subjecting compound (1), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystal thereof, preferably a benzyl alcohol solvate crystal of compound (Ia), to a deprotection reaction, The compound (ii), its pharmaceutically acceptable salt, its solvate, or crystal thereof, which is the antibacterial agent disclosed in Japanese Patent No. 294970, is obtained.

The deprotection reaction is performed according to methods well known to those skilled in the art. In this reaction, a noble metal catalyst such as a nickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalyst, a platinum catalyst and a palladium catalyst is used. Palladium catalyst and nickel catalyst are preferably used. More preferable are tetrakis (triphenylphosphine) palladium, acetic acid (triphenylphosphine) palladium, and acetic acid (triethylphosphite) palladium. An additive (preferably triphenylphosphine or the like) may be added to the mixed solution containing radium. More preferably, a reducing agent for reducing and removing the protecting group and a nucleophilic reagent (aryl group trapping agent) are added to the palladium catalyst. Examples of the reducing agent include hydrogen, metal hydride, and the like, and preferably hydrogenated tri-n-butyltin. Examples of nucleophiles include carboxylates (eg, sodium 2-ethylhexanoate), 1,3-dicarboxyl compounds (eg, Meldrum's acid, dimedone and malonic acid esters), secondary amines (eg, Jetylamine, etc.) and aromatic amines.

 In consideration of environmental aspects and reaction yield, a combination of a palladium catalyst (eg, tetrakis (triphenylphosphine) palladium) and an aromatic amine (eg, Ryoji phosphorus derivative) is more preferable as a deprotection reagent. . The ar phosphorus derivatives include: arline, N-methylarine, N-ethylaniline, Ν, Ν-dimethylaniline, 0—, m—or ρ—toluidine, 0—, m— or p-amino-idine. In particular, N-ethylaline is particularly preferable. When the amount of Pd reagent used is significantly reduced by using N-ethylaline (e.g., less than 0.01 molar equivalent to the compound (I), preferably 0. The deprotection reaction proceeds at a high yield even at 005 monorequivalents or less, more preferably from 003 to 0.001 monoequivalents. In addition, the generation rate of by-products derived from the protecting group and the aniline reagent is low, and the handling operation of the compound (II) deposited after deprotection is also good, which is suitable as a mass production method.

 The amount of the aromatic amine (eg, a phosphorus derivative) to be used is 1 to 20 mole equivalents, preferably 5 to 15 equivalents, relative to Compound (I).

 The solvent used in the deprotection reaction may be any solvent that is used in ordinary reactions. Acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol, water and the like are preferable. These solvents may be used alone or in combination of two or more. Particularly preferred is a combination of tetrahydrofuran and water, preferably tetrahydrofuran: water = 1: 1 to 10: 1.

Compound (1), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystal thereof A nuclear reagent is added to the solvent and the reaction system (eg, reaction mixture and vessel) is preferably filled with nitrogen.

 The reaction temperature is about 20-50 ° C, preferably in the range of 0-30 ° C.

 The reaction time is usually several minutes and several tens of hours, preferably in the range of 1 to 3 hours. The present invention further provides the crystals of compounds (IV-a) and (V-a), which are synthetic intermediates of compound (Ia).

 [Chemical 19]

 (IV- a)

(Ac = acetyl; Boc = t butoxycarbol)

 (1) Compound (IV—a) crystals

 This crystal has a major peak in the powder X-ray diffraction pattern with diffraction angles of at least 2 Θ = 6.26, 12.50, 18.24, 18.80, 23.90, and 26.86 (unit: degree) It exists in the vicinity. More specifically, the pattern shown in FIG. 3 is shown. The crystals of compound (IV-a) may be solvates (eg, hydrates, alcohol solvates)!

 (2) Compound (V—a) crystals

 This crystal has at least 2 Θ = 10.24, 12.26, 13.34, 17.32, 20.84, 21.22, 21.72, and 22. 28 (Unit: degree) More specifically, the pattern shown in FIG. 4 is shown. The crystals of compound (Va) may be solvates (eg hydrates, alcohol solvates).

As the crystals of compound (IV-a), the crystals of compound (V-a) are preferred as shown in Examples below. After deprotecting with an acid, more preferably with an inorganic acid (e.g. hydrochloric acid), the reaction solution is adjusted to pH with an alkali (preferably 2 to 3) and precipitated, then dried and concentrated by a conventional method, and organic It can be crystallized from a solvent (preferably an ethyl acetate-toluene system). In addition, H NSO NHBoc is added to the compound (VI-a).

 After reacting to produce compound (Va), it may be subjected to a deprotection reaction as described above without isolation. In addition, when there is a possibility that a by-product derived from the amino protecting group is generated during the deprotection reaction, a radical trapping agent may be preferably used in combination. An example of the radical trapping agent is dibutylhydroxytoluene.

 In this production method, by using the high-purity compound (1) obtained above, a pharmaceutically acceptable salt, a solvate thereof, or a crystal thereof, water and an organic solvent after the deprotection reaction, preferably In the impurity extraction operation using dichloromethane, it became possible to prepare an aqueous solution in which the target compound (Π) was dissolved at a high concentration. As a result, concentration and column chromatography, which have been indispensable in the post-treatment process, are no longer essential operations, and the target pyrrolidylthio strength rubapenem derivative (II), its pharmaceutically acceptable salt, its solvent It became possible to easily isolate hydrates or crystals thereof. Therefore, it is also useful as an industrial production method.

 Examples are shown below.

Example 1

[Chemical 11]

A 2-propanol hydrate crystal (3.340 g, equivalent to 3.137 g in solvent-free equivalent) of the compound (Ia) described in WO2004Z72073 is dissolved in ethyl acetate (67 ml), and then ethyl acetate and isopropanol are dissolved. Was distilled off to obtain an ethyl acetate concentrate (4.551 g). Ethyl acetate (3.14 ml), benzyl alcohol (3.14 ml), and toluene (12.55 ml) were added thereto, and the mixture was stirred at room temperature for 2 hours and then at 5 ° C for 1 hour. The precipitated crystals were separated by filtration, washed with toluene (6.26 ml), air-dried, and benzyl alcohol solvate crystals of compound (I a) (3.668 g, 3.037 g in solventless form) Corresponding benzyl alcohol (l.Omol) was obtained. Yield: 96.8%

Mp. 74.9 ° C

Elemental analysis for C H N 0 S-1.0C H O -0.2 H 0

 22 31 4 8 2 7 8 2

 Calcd: C: 53.15, H: 6.06, N: 8.55, S: 9.79

 Found: C: 53.19, H: 6.12, N: 8.65, S: 9.85

Powder X-ray diffraction: The chart is shown in Fig. 1 and the peak value is shown in Fig. 2.

 For other alcohol solvate crystals of compound (I a) (solvent examples: 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol, 1-propanol), 25 ° C, 1 When stored in a general environment at atmospheric pressure, a phenomenon was observed in which the amount of solvent contained decreased due to deflation over time. However, benzyl alcohol hydrate crystals did not show such a phenomenon even when handled for several days, and it was found that the stability was high.

Example 2

 Amorphous and powdery compound (I a) (100 mg) was dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) was added and stirred at room temperature for 1 hour, then 5 ° C was left for 2 days. The precipitated crystals were separated by filtration and air-dried to obtain a benzyl alcohol solvate crystal (79 mg) of compound (Ia) showing substantially the same powder X-ray pattern as in Example 1.

Example 3

[Chemical 12] e ₃ Si QHH ^H s

° 删₂關₂

 (I I 卜 a) (IV-a) (I -a)

(Where, \ 16 = methyl; Ph = ferrule)

Hydroxyl-protected enol phosphite (III—a) 595 mg (1 mmol) and thiol compound (IV—a) 345 mg (1.1 mmol) in N-dimethylacetamide 2 ml solution After distilling 0.168 ml (1.2 mmol) of diisopropylamine at 12 to 8 ° C, the mixture was stirred at the same temperature for 1 hour and 30 minutes. At this point, it was confirmed by HPLC that the condensation reaction had progressed 92%. Reaction solution The solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water, 5% sodium bicarbonate water and water, then dried over sodium sulfate, and the solvent was distilled off. The residue was dissolved in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol and the crystals obtained in Example 2 were seeded and stirred at room temperature for 2 hours. Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and then cooled to 5 ° C. After filtration and drying, 554 mg (85%) of benzyl alcohol solvate crystals of compound (Ia) showing substantially the same powder X-ray pattern as in Example 1 were obtained.

Example 4

[Chemical 13]

 (lll -b) (I Va) (I -a) Enolphosphe -Hill b) 500 mg (1 mmol) and thiol compound (IV—a) 345 mg (ll m mol) N-dimethylacetamide 2 Diisopropylamine 0.168 ml (1.2 mmol) was added dropwise to the ml solution at −15 ° C., and the mixture was stirred at the same temperature for 3 hours. At this point, the formation of compound (Ia) was confirmed (HP LC quantification: 92%). The reaction solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water, 5% sodium bicarbonate water and water, then dried over sodium sulfate, and the solvent was distilled off. The residue was dissolved in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol and the crystals obtained in Example 2 were added as seed crystals, and the mixture was stirred at room temperature for 2 hours. Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and then cooled to 5 ° C. After filtration and drying, 548 mg (84%) of a benzyl alcohol hydrate crystal of the compound (Ia) showing substantially the same powder X-ray pattern as in Example 1 was obtained.

Example 5

[Chemical 14]

化合物（I a)のべンジルアルコール和物結晶 2.0 g (3.06 mmol)をテトラヒドロフラ ン 12 mlに溶解させ、イソプロパノール 1 ml, N—ェチルァ-リン 3.71 ml (30.62 mmol ；),水 4 ml, Pd(PPh ) (Ph =フエ-ル） 7.1 mg (0.2 eq)を順次加え、窒素気流下 25°C

Compound (Ia) benzyl alcohol solvate 2.0 g (3.06 mmol) is dissolved in tetrahydrofuran 12 ml, isopropanol 1 ml, N-ethylaline 3.71 ml (30.62 mmol;), water 4 ml, Pd (PPh) (Ph = fuel) 7.1 mg (0.2 eq) was added in succession and under nitrogen flow at 25 ° C

 3 4

For 3 hours. Next, the mixture was allowed to stand at the same temperature for 1.5 hours and at 5 ° C for 16 hours, and then the precipitate was filtered and dried to obtain 1.26 g (94%) of the desired product (11).

Example 6

[Chemical 20]

 (Ii) a (I I) The same reaction as in Example 5 was carried out by reducing the amount of Pd catalyst used.

 Compound (I a) (however, using isopropyl alcohol hydrate crystals) 500 mg is dissolved in 2 ml of tetrahydrofuran (THF), 10 equivalents of N-ethylaline, 2 ml of THF and 1 ml of H 0 in this order.

 2

In addition, vacuum degassing and nitrogen substitution were repeated 3 times. Pd (PPh) 0.002 equivalent, T

 3 4

 2 ml of HF was added in order, and the degassing of the charged solution and nitrogen replacement were repeated three more times. Compound (II) began to crystallize when reacted for about 1.5 hours at room temperature, in a nitrogen atmosphere and under rotor stirring conditions. The disappearance of the raw materials and reaction intermediates was confirmed by HPLC, and dimethylformamide (DMF) was added 3 hours after the start of the reaction to homogenize the reaction solution. The production rate of compound (II) calculated from this reaction solution was 92%.

Comparative Example 1

 When the reaction of Example 6 was carried out using N-methylaline instead of N-ethylaline, the yield of compound (II) was 89%. The properties of the precipitated compound (II) were more viscous than those using N-ethylaline, partly agglomerated, and part of it adhered to the reaction vessel wall.

Furthermore, instead of N-ethylaline, other electron-donating group-substituted alines (eg, Ν, Ν -dimethylaline, toluidine, acidin) were used for the same reaction. In both cases, the production rate of compound (II) was lower than when Ν-ethylaline was used. (Yield 0-86%).

Comparative Example 2

 The reaction of Example 6 was carried out in the same manner using aline instead of N-ethylaline (provided that the solvent used was THF (12V) monohydrate (2V)). As shown below, when the amount of Pd catalyst used was reduced, a large amount of by-products were generated and the production rate of compound (II) was significantly reduced.

[table 1]

Pd (PPh ₃ ) ₄ reaction time Formation rate of compound (11)

 (eq) (h) (%)

 0.0200 0.5 86

 0.0100 0.5 84

 0.0050 1.5 83

 0.0025 5.0 70 Example 7

[Chemical 21]

NH ₂ S0 ₂ NHBoc (1.35 eq)

1J∞ " _U ^HCI _u ^ NHS0 ₂ NH ₂

2) NaOH aq ^ (8 eq) HS ^d

 3) conc.HCI (6 eq) Alloc

^ · ₈ Alloc = -COOCH2CH = CH2

(1) Synthesis of 7 (Crystal of Compound (V—a))

Compound synthesized by the method described in JP-A-5-294970 or the above route 6 26.7 g (0.1 mol, 97.1% purity), H NSO NHBoc (Boc = t-butoxycarbol) 26.49 g (1.35

twenty two

eq), and 400 ml of ethyl acetate containing 32 g (1.22 eq) of PPh (triphenylphosphine)

 Three

To the solution, 23.63 g (1.2 eq) of DIAD (jetylazodicarboxylate) was added dropwise at room temperature over 30 minutes. After stirring at the same temperature for 16 hours, the ethyl acetate is distilled off under reduced pressure and replaced with 100 ml of toluene. The precipitated reduced form of DIAD was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the eluate of _n- hexane-ethyl acetate 2: 1 was concentrated to obtain 48..5 g of the intended product. Crystallization from ethyl ether gave 27.12 g (62%) of crystals.

Mp. 115.

 Anal for C H N O S (FW 437.53), Calcd .; C, 43.92, H, 6.22, N, 9.60, S, 14.66

 16 27 3 7 2

 Found; C, 43.87, H, 6.20, N, 9.67, S, 14.37

^J H NMR (CDC1): δ 1.51 (s, 9H), 2.34 (s, 3H), 2.53-2.63 (m, 1H), 3.19-3.25 (m, 1

 Three

 H), 3.57-3.63 (m, 1H), 3.90—4.04 (m, 2H), 4.20-4.27 (m, 3H), 4.52-4.54 (m, 3H), 5.21-5.32 (m, 3H), 5.82—5.96 (m, 4H)

λ ^MeOH ε (nm); 4,310 (231)

 max

v ^Nuio1 3374, 3195, 1721, 1678 cm— ¹

 max

[a] ²² ° +4.6 ⁺ 0.5. , [A] ²² ° +1.2 ⁺ 0.4. (Me〇H, C = 1.001%)

 365 436

Fig. 4 shows the powder X-ray diffraction data. The peak with peak number 23 is the peak derived from the aluminum used in the measurement.

(2) Synthesis of 6 to 8 (crystal of compound (VI—a))

 Compound 6 26.48 g (0.1 mol, 94% purity), H NSO NHBoc 24.89 g (1.35 eq), PPh 29.

 2 2 3

To a 244 ml solution of 57 g (1.2 eq) of ethyl acetate, 22.80 g (1.2 eq) of DIAD was added dropwise at room temperature over 30 minutes. After stirring at the same temperature for 16 hours, ethyl acetate was distilled off under reduced pressure and dissolved in 260 ml of methanol. Methanesulfonic acid (3.8 ml, 1.0 eq) was added, and the mixture was stirred at 65-70 ° C for 4 hours. After cooling, distill off the solvent, add to 260 ml (2.2 eq) of 0.5N NaOH solution and wash twice with 260 ml of ethyl acetate. Back extraction was performed from each ethyl acetate layer with 234 ml (2 eq) of 0.5N NaOH solution. The aqueous layers were combined, acidified with hydrochloric acid, and extracted twice with 260 ml of ethyl acetate. After washing with 130 ml of water, merge, dry with Na 2 SO and concentrate the solvent under reduced pressure to obtain 6.61 g (66.1%) of 8 crystals. Similar results were obtained when hydrochloric acid water or hydrochloric acid / methanol solution was used instead of methanesulfonic acid.

 Mp. 107-109 ° C

 Anal for C H N O S (FW 295.38), Calcd .; C, 36.60, H, 5.80, N, 14.23, S, 21.71

 9 17 3 4 2

 Found; C, 36.58, H, 5.75, N, 14.14, S, 21.82

 1H NMR (CDC1): δ 1.72-1.74 (m, 2H), 2.55-2.64 (m, 1H), 3.11-3.22 (m, 1H), 3.2

 Three

 4-3.35 (m, 2H), 3.41—3.49 (m, 1H), 4.02—4.09 (m, 2H), 4.58—4.60 (m, 2H), 4.71 (3, 2H), 5.24-5.35 (m, 2H ), 5.87—6.00 (m, 2H)

[a] ²³ ° -49.7 + 0.9. (MeOH, C = 1.004%)

 D

Figure 3 shows the powder X-ray diffraction data. The peak with peak number 20 is the peak derived from the aluminum used in the measurement.

(3) Synthesis of 7 to 8

 To a solution of 77.5 g (17.14 mol) of crystals in 15 ml of methanol was added 30.34 ml (4 eq) of a 2.26 N HC1 / methanol solution at room temperature, and the mixture was stirred at 40 ° C for 4.5 hours. After cooling, the mixture was salted with 10% NaOH aqueous solution to pH 2.5 and extracted three times with 50 ml of ethyl acetate. Each ethyl acetate layer was washed 3 times with 38 ml of 6% saline. Merged with ethyl acetate layer, dried NaSO, concentrated solvent,

 Four

Crystallization from the ethyl acetate-toluene system gave 84.77 g (94.2%).

Claims

The scope of the claims  [1 set:  [Chemical 1]

Wherein R is hydrogen or a hydroxy protecting group; R ¹ is a carboxy protecting group; Ph is  Compound (III) represented by the formula: [Chemical 2]

(Wherein R ² is an amino protecting group)  Wherein the compound (IV) or a pharmaceutically acceptable salt thereof is reacted in the presence of a secondary amine, and then the hydroxy protecting group is optionally deprotected,  [Chemical 3]

(Wherein R ¹ and R ² are as defined above)  Or a pharmaceutically acceptable salt, solvate or crystal thereof.  [2] The production method according to claim 1, wherein the secondary amine is diisopropylamine. [3] The production method according to claim 1 or 2, wherein R ¹ is CH ² CH═CH; R ² is COOCH CH═CH.  2 2 2 2 [4] After obtaining the compound (I), its pharmaceutically acceptable salt, its solvate or crystals thereof by the method according to any one of claims 1 to 3, it is subjected to a deprotection reaction. It is characterized by formula:  [Chemical 4]

Or a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula:  [Chemical 5]

A solvate crystal of the compound (Ia) represented by the formula (provided that the solvent is an optionally substituted benzyl alcohol). 6. The crystal according to claim 5, which is a benzyl alcohol solvate crystal. 4. Crystalline content according to claim 3, which is 1 to 10 molar equivalents relative to compound (I). The crystal according to claim 6 or 7, wherein in the powder X-ray diffraction pattern, main peaks are present in the vicinity of diffraction angles 20 = 7.6, 17.7, 18.5, 1 9.5, 19.9, 21.3, 23.8 (unit: degree). A compound characterized by deprotecting the crystal according to any one of claims 5-8: [Chemical 6]

(11), a pharmaceutically acceptable salt thereof, or a solvate thereof Method.  [10] After obtaining the compound (I), a pharmaceutically acceptable salt or a solvate thereof by the method according to any one of claims 1 to 3, this is substituted, and The compound according to claim 9, wherein the compound (I) is substituted by crystallization in benzyl alcohol to obtain a benzyl alcohol solvate crystal, which is deprotected. I) A method for producing a pharmaceutically acceptable salt or solvate thereof.  [11] Formula:

(Wherein R ¹ is a carboxy protecting group; R ² is an amino protecting group)  A compound represented by the formula, a solvate thereof, or a crystal thereof is deprotected in the presence of a Pd catalyst and N-ethylyl-phosphorus:  [Chemical 8]

Or a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. The production method according to claim 11, wherein R ¹ is CH ² CH═CH; R ² is COOCH CH═CH.  2 2 2 2  [13] The process according to claim 11, wherein the amount of the Pd catalyst used is 0.01 molar equivalent or less relative to compound (I).  [14] The production method according to claim 11, wherein the amount of the Pd catalyst used is 0.005 molar equivalent or less relative to compound (I). [15] Formula: [Chemical 9]

A crystal of the compound represented by In the powder X-ray diffraction pattern, the main peak is the diffraction angle 20 = 6. 24, 18. 80, 23. 90, and 26. 86 (in degrees), Ligation o Formula:  [Chemical 10]

(In the formula, Ac is acetyl; Boc is t-butoxycarbol) A crystal of the compound represented by In the powder X-ray diffraction pattern, the main peaks are diffraction angles 2 0 = 10.24, 12.26, 13.34, 17.32, 20.84, 21.22, 21.72, and 22.28 (units) The crystal according to claim 17, which exists in the vicinity of: